Clinical responses to new therapies for castration resistant prostate cancer (CRPC) which potently inhibit ligand synthesis (e.g. abiraterone) or block the androgen receptor (AR) ligand binding domain (LBD) (e.g. MDVS100) have been impressive. However, patients invariably progress. Defining mechanisms of resistance to these newly introduced therapies is crucial if long-term control or cure of CRPC is to be achieved. Hypothesis. Our primary hypothesis is that the AR axis remains a primary driver of resistance to new agents targeting the AR pathway, and that increasingly potent abrogation of the AR-LBD interaction will result in expression of ligand independent AR variants (ARVs) as important components of resistance. We hypothesize that patient-specific differences in the AR-axis dictate sensitivity to agents targeting these pathways, and that tumor-specific differences in intratumoral steroidogenesis and expression of AR or ARVs can be exploited as indicators of response to agents targeting the AR axis and crosstalk pathways in CRPC. Specific Aim 1. Determine the efficacy of abiraterone in suppressing tumor androgens in a clinical trial of CRPC, and the role of steroidogenesis, AR or ARVs as mechanisms of resistance at progression. Specific Aim 2. Determine how tumor-specific differences in the AR-axis influence response and resistance to novel agents targeting the AR pathway, including LBD-targeted (e.g., abiraterone, MDV3100) and non-LBD-targeted AR inhibitors (e.g., EPI-002, T6). The goals of this Aim are to determine how the expression of AR-axis components associates with resistance to AR pathway inhibition, and whether LBD-deleted ARVs emerge as key targets in tumors that progressed on AR-LBD directed therapy. Specific Aim 3. Determine whether transgenic expression of the CRPC-specific ARv567 variant influences tumor progression or response to PI3K inhibition in tumors driven by the loss of PTEN. As up to 40% of primary and 70% of metastatic prostate cancers exhibit PTEN loss or PI3K/AKT activation20,21 the goals of this Aim are to determine how induction of ARVs will alter CRPC progression in this setting and/or influence treatment strategies targeting the AKT/PI3K pathway. Our overarching goal is not only to elucidate mechanisms of response to specific therapies, but in so doing, to better understand how the AR, despite continuing to remain the dominant target of therapy in PCa, continues to elude increasingly potent agents and multi-targeted treatment strategies.